Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].N(C(CCCCCCCCCC)CCCCCNC1C=CC(C(O)=O)=CC=1)=[N+]=[N-]>CN(C)C=O>[N:34]([CH:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)OCC)cc1)OS(C)(=O)=O
Agent: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)O)cc1)N=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCC(CCCCCNc1ccc(C(=O)OCC)cc1)N=[N+]=[N-]

Procedure:
A solution of 6.4 g. of ethyl 4-(6-methanesulfonyloxyhexadecylamino)benzoate and 1.9 g. of sodium azide in 65 ml. of dimethylformamide is stirred at ambient temperature for 16 hours, poured into 200 ml. of water, and extracted with chloroform. The organic extract is washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated. Crystallization of the residue from hexane yields the product. The ester is hydrolyzed to 4-(6-azidohexadecylamino)benzoic acid using the procedure of Example 10.
Reaction SMILES: C1COC2C=CC(NC3C(F)=CN=C(NC4C=CC=C(O)C=4)N=3)=CC=2O1.[CH3:27][C:28]1[CH:29]=[C:30]([CH:32]=[C:33]([CH3:37])[C:34]=1[O:35][CH3:36])[NH2:31].[Cl:38][C:39]1[N:44]=[C:43](Cl)[C:42]([F:46])=[CH:41][N:40]=1>>[Cl:38][C:39]1[N:44]=[C:43]([NH:31][C:30]2[CH:32]=[C:33]([CH3:37])[C:34]([O:35][CH3:36])=[C:28]([CH3:27])[CH:29]=2)[C:42]([F:46])=[CH:41][N:40]=1
Reactant: COc1c(C)cc(N)cc1C
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Oc1cccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1
Product: COc1c(C)cc(Nc2nc(Cl)ncc2F)cc1C

Procedure:
In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-N2-(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 3,5-dimethyl-4-methoxyaniline (400 mg, 2.6 mmol) and 2,4-dichloro-5-fluoropyrimidine (200 mg, 1.2 mmol) gave 2-chloro-N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine. The reaction of 2-chloro-N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-4-pyrimidineamine and 3-(methoxycarbonylmethyleneoxy)aniline (650 mg, 3.6 mmol) gave N4-(3,5-dimethyl-4-methoxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (180 mg, 35%). 1H NMR (CD3OD): δ 2.20 (s, 6H), 3.70 (s, 3H), 3.74 (s, 3H), 4.52 (s, 2H), 6.76 (ddd, J=0.9, 2.4 and 8.4 Hz, 1H), 7.03-7.08 (m, 2H), 7.24 (m, 3H), 7.96 (d, J=5.4 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −162.92; LCMS: ret. time: 23.13 min.; purity: 100%; MS (m/e): 427.04 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[S:16][C:17]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=2[N:19]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.O>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:15]2[S:16][C:17]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](N)C1
Reactant: Fc1ccc2nc(Cl)sc2c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccc(F)cc3s2)C1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl(trans-3-aminocyclobutyl)carbamate (0.099 g, 0.533 mmol), 2-chloro-6-fluoro-1,3-benzothiazole (0.100 g, 0.533 mmol) and diisopropylethylamine (0.185 ml, 1.066 mmol) in DMSO (0.5 mL) contained in a microwave vial was capped and heated to 120° C. for 2 hrs. The mixture was diluted with water and extracted with EtOAc. EtOAc extract was concentrated to give crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate. To the crude tert-butyl(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)carbamate was added hydrogen chloride, 4N in 1,4-dioxane (10 ml, 40.0 mmol) and the resulting solution stirred at room temperature for 2 h and concentrated to afford crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride. The crude trans-N1-(6-fluorobenzo[d]thiazol-2-yl)cyclobutane-1,3-diamine hydrochloride was added to mixture of methyl (2-chloropyridin-3-yl)(methyl)carbamate, INTERMEDIATE 40, (0.107 g, 0.533 mmol), chloro(2-dicyclohexylphosphino-3,6-dimethoxy-2′-4′-6′-triisopropyl-1,1′-biphenyl)]2-(2-aminoethyl)Ph)Pd(II) (0.021 g, 0.027 mmol), and sodium tert-butoxide (0.261 ml, 2.132 mmol) in dioxane (10 mL). The mixture was stirred at 100° C. for 2 h and concentrated. The residue was diluted with water and extracted with EtOAc. EtOAc extract was concentrated and residue purified with ISCO on silica gel column eluting with 0-80% EtOAc/hexanes to give the title compound 3-(trans-3-((6-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.092 g, 0.249 mmol, 46.7% yield). m/z: 370.1 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 8.07 (dd, J=5.18, 1.27 Hz, 1 H), 7.49 (dd, J=8.90, 4.79 Hz, 1 H), 7.32 (dd, J=8.12, 2.64 Hz, 1 H), 7.17 (dd, J=7.73, 1.27 Hz, 1 H), 6.97-7.07 (m, 2 H), 5.90 (br. s., 1 H), 5.33-5.50 (m, 1 H), 4.48-4.74 (m, 1 H), 3.48-3.67 (m, 2 H), 3.43 (s, 3 H), 2.34-2.63 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:5]=[C:6]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:7]=1[O:8][CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][CH2:44][N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55]>CC(C)=O>[C:46]1(=[O:55])[N:45]([CH2:44][CH2:43][CH2:42][O:1][C:2]2[CH:3]=[C:4]([C@H:18]3[CH2:22][CH2:21][C@H:20]([C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[O:19]3)[CH:5]=[C:6]([S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:7]=2[O:8][CH2:9][CH2:10][CH3:11])[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]12
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCC
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(OCCCN2C(=O)c3ccccc3C2=O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCC
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of (±)-trans-2-(3-hydroxy-4-propoxy-5-propylsulfonylphenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (2.80 g, 5.66 mol) in acetone (40 ml) were added potassium carbonate (1.01 g, 7.36 mol) and N-(3-bromopropyl) pthalimide (2.06 g, 8.50 mmol). The reaction mixture was refluxed for 16 h. The reaction mixture was cooled to room temperature and acetone was removed, water was added and extracted with ethyl acetate (120 ml), dried (Na2SO4), filtered and concentrated. The crude product was purified on silica gel column using Ethyl acetate:light petroleum (2:5) to give (±)-trans-2-[3-(3-pthalimidopropoxy)-4-propoxy-5-propylsulfonyl phenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran as solid (3.71 g, 94%). TLC: Ethyl acetate:light petroleum (2:1), Rf=0.5 ; m.p. 195-196° C. 1H NMR (CDCl3, 200 MHz): δ 1.05 (t, J=7.14 Hz, 3H), 1.08 (t, J=6.66 Hz, 3H), 1.68-2.06 (m, 6H), 2.2-2.3 (m, 2H), 2.4-2.55 (m, 2H), 3.35 (m, 2H), 3.83 (s, 3H), 3.9 (s, 6H), 3.95 (t, J=6.6 Hz, 2H), 4.15 (t, J=6.13 Hz, 4H), 5.2 (m, 2H), 6.58 (s, 2H), 7.23 (d, J=1.5 Hz, 1H), 7.45 (d, J=1.51 Hz, 1H), 7.7 (m, 2H), 7.85 (m, 2H); IR (neat): 3010, 2975, 1775, 1715, 1600, 1490, 1380 cm−1 FAB Mass: 681(M+); HRMS: calculated. 681.260769; found. 681.265005.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[NH:3][C:2]1=[O:9].C(=O)([O-])[O-].[K+].[K+].[P:16](Cl)([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[S:17]>CC(C)=O>[CH2:19]([O:18][P:16]([O:9][C:2]1[S:1][C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[N:3]=1)([O:21][CH2:22][CH3:23])=[S:17])[CH3:20]
Reactant: O=c1[nH]c2c(s1)CCC2
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)Oc1nc2c(s1)CCC2

Procedure:
A mixture of 21 g of 2,3,5,6,-tetrahydro-4H-cyclopentathiazoline-2-one, 21 g of potassium carbonate and 300 ml of acetone was refluxed for 1 hour and after the addition of 28 g of O,O-diethyl chlorothiophosphate thereto, the mixture was refluxed for 1 hour. The mineral salts were filtered off and the filtrate was distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate to obtain 4g of 2-(diethoxythiophosphoryloxy)-5,6-dihydro-4H-cyclopentathiazole with a refractive index of nD28 = 1.5348.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)(=[O:29])[CH2:19][C:20]1[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:22]([OH:24])=[O:23]>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:18]([CH2:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:29])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)Cc2ccccc2C(=O)O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 60 %

Procedure:
2-Amino-4-methylthiazole-5-carboxylic acid benzylamide (0.25 g, 1.00 mmol) and homophthalic acid (0.18 g, 1.00 mmol) were melted together at 170° C. for 2 hours. A colorless solid formed after the melt was cooled to ambient temperature. The solid was washed with ether (50 mL) and then crystallized from ethyl acetate/methanol to afford the title compound in 60% yield; 1H NMR (DMSO-d6, 300 MHz) δ 12.37 (s, 1H), 8.48 (t, J=5.9 Hz, 1H), 7.88 (dd, J=1.4, 7.6 Hz, 1H), 7.50 (dt, J=1.4, 7.6 Hz, 1H), 7.40-7.15 (m, 7H), 4.34 (d, J=5.9 Hz, 2H), 4.14 (s, 2H), 2.45 (s, 3H); MS (ES+) m/z 410.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[P].I.[ClH:26]>C(O)(=O)C.CO.CCOCC>[ClH:26].[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:18][CH:19]=1
Reactant: OC(Cc1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: I
Agent: [P]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOCC
Product: Fc1ccc(C(Cc2ccncc2)c2ccc(F)cc2)cc1
Yield: 87 %

Procedure:
A mixture of 15.05 g (0.048 mole) of α,α-bis(4-fluorophenyl)-4-pyridineethanol, 3.2 g (0.1 mole) of phosphorus and 50 ml of 56.9% hydrogen iodide in 150 ml of glacial acetic acid was heated at reflux for 11 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in a mixture of methanol and ether, and an excess of ethereal hydrogen chloride was added. The solvent was removed in vacuo, and the residue was recrystallized from a mixture of acetonitrile and ether to give 13.89 g (87% yield) of title compound as a white, crystalline solid, mp 197°-199° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Cl)[CH:17]=1.O>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:22][C:18]1[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=1)[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: ClCc1cccnc1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(ccn2Cc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.2 %

Procedure:
5-Nitroindole (0.49, 3 mmol) was treated with sodium hydride (0.198 g, 6.6 mmol) in dry dimethylformamide (20 ml). After 15 min at room temperature, 3-picolyl chloride hydrochloride (0.49 g, 3 mmol) was added and the mixture was stirred at room temperature for 24 h, then poured into water. The precipitate was filtered off, washed with water and dried to give the tide compound (0.67 g, 88%), m.p. 131-4° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH:10]2[N:22]([C:25](=[O:42])[CH:26]([NH:31]C(OCC3C=CC=CC=3)=O)[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[CH:10]2[N:22]([C:25](=[O:42])[CH:26]([NH2:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:24][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(NC(=O)OCc1ccccc1)C(C)(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(N)C(C)(C)C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of compound 23 (2.4 g, 4.1 mmol) and 10% Pd-on-carbon (wet, 500 mg) in MeOH/EtOAc (1:1, 100 mL) was pressurized to 50 PSI H2 and shaken for 3 h using a Parr apparatus. The reaction mixture was filtered through a pad of celite and the solids were washed with EtOAc. The clarified filtrate was concentrated in vacuo to give 33 as a white solid (1.84 g, 100%). The crude product was used without further purification. Mass spectrum, m/z [454.2] (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:25][S:26]([CH2:29][C:30]#[N:31])(=[O:28])=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C.N1CCCCC1.O>[CH2:18]([NH:25][S:26](/[C:29](=[CH:8]/[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:12]([OH:13])=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=1)/[C:30]#[N:31])(=[O:28])=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#CCS(=O)(=O)NCc1ccccc1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)c1cc(/C=C(\C#N)S(=O)(=O)NCc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 100 °C

Procedure:
A mixture of 250 mg of 3,5-di-t-butyl-4-hydroxybenzaldehyde and 230 mg of N-benzyl cyanomethyl sulfonamide in 2 ml of ethanol with 2 drops of piperidine was heated at 100° C. for 3 hours. The cooled mixture was then diluted with 10 ml of water and extracted with 50 ml of ethyl acetate. The organic extract was then washed with brine, dried over sodium sulfate, filtered and concentrated. Crystallization of the crude with ethyl acetate and hexane yield 206 mg of the titled compound.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:22])[N:5]([CH3:21])[C:6]([OH:20])=[C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[C:8]=1[CH3:9])#[N:2].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1.CC(N(C)C)=O>[C:1]([C:3]1[C:4](=[O:22])[N:5]([CH3:21])[C:6]([OH:20])=[C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][O:19][S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])=[CH:14][CH:13]=2)[C:8]=1[CH3:9])#[N:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1c(N=Nc2ccc(CO)cc2)c(O)n(C)c(=O)c1C#N
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: Cc1c(N=Nc2ccc(COS(=O)(=O)c3ccccc3)cc2)c(O)n(C)c(=O)c1C#N
Yield: 49.3 %

Procedure:
14.9 g of Compound [2-a] was benzenesulfonylated in the same manner as described in Step 1-h using 12 g of benzenesulfonyl chloride in 50 ml of pyridine and 20 ml of dimethylacetamide to obtain 10.8 g of Compound [2-b].
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[CH:13]>CN(C=O)C.CCN(CC)CC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N+:9]([C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([C:13]#[C:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:8]=1)([O-:11])=[O:10]
Reactant: C#Cc1ccccn1
Reactant: Nc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc([N+](=O)[O-])cc1C#Cc1ccccn1
Temperature: 60 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
To the solution of 2-iodo-4-nitroaniline (3.0 g, 11 mmol) in DMF (60mL) and Et3N (60 mL) was added 2-ethynylpyridine (3.0 g, 45 mmol), Pd(PPh3)2Cl2 (600 mg) and CuI (200 mg) under N2. The reaction mixture was stirred at 60° C. for 12 h. The mixture was diluted with water and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuum. The residue was purified by chromatography on silica gel (5-10% ethyl acetate/petroleum ether) to afford 4-nitro-2-(pyridin-2-ylethynyl)aniline (1.5 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1 H), 8.13 (d, J=2.1 Hz, 1 H), 7.98 (d, J=1.8, 6.9 Hz, 1 H), 7.87-7.80 (m, 2 H), 7.42-7.39 (m, 1 H), 7.05 (brs, 2 H), 6.80 (d, J=6.9 Hz, 1 H).
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=[O:4].C(=O)C.C(O)(C)C.[P:14](=[O:18])([OH:17])([OH:16])[OH:15]>>[P:14]([O-:18])([OH:17])([OH:16])=[O:15].[C:2]([OH:6])(=[O:5])[CH:3]=[O:4]
Reactant: O=P(O)(O)O
Agent: CC=O
Agent: O=CC(=O)O
Solvent: O
Solvent: CC(C)O
Product: O=P([O-])(O)O
Temperature: 40 °C
Reaction time: 20 h

Procedure:
32.3 g (0.100 mole) of 4'-methoxy-4-diazodiphenylamine hydrogensulfate was dissolved in 70 ml of an 85% phosphoric acid solution. Then 6.64 g (0.0700 mole) of glyoxylic acid monohydrate (97%) was added to this solution and the mixture was stirred at 40° C. for 20 hours. Then 3.96 g (0.0900 mole) of acetaldehyde was added to the reaction mixture and the mixture was stirred at 40° C. for additional 20 hours. Thereafter, the reaction solution was poured into 800 ml of isopropyl alcohol while stirring, to give yellow precipitate. The yellow precipitate was obtained by filtering and washed with isopropyl alcohol, to give dihydrogenphosphate of of a condensate of 4'-methoxy-4-diazodiphenylamine with glyoxylic acid.acetaldehyde.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[NH2:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[C:8]=1[C:22]#[N:23]>C(O)C>[NH2:6][C:7]1[N:11]([CH3:12])[N:10]=[C:9]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[C:8]=1[C:22]([NH2:23])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: Cn1nc(-c2ncc([N+](=O)[O-])n2C)c(C#N)c1N
Solvent: CCO
Product: Cn1nc(-c2ncc([N+](=O)[O-])n2C)c(C(N)=O)c1N

Procedure:
Another grouping present in these novel compounds, namely the 4-carbonitrile group, can also be utilized to prepare derivatives. This carbonitrile group can be readily hydrolyzed to the 4-carboxamide grouping by allowing the carbonitrile to react with concentrated sulfuric acid in absolute ethanol. Illustratively, when 5-amino-1-methyl-3-(1-methyl-5-nitro-2-imidazolyl)pyrazole- 4-carbonitrile is allowed to react with concentrated sulfuric acid in absolute ethanol at steam bath temperature for about one hour, there is obtained 5-amino-1-methyl-3-(1-methyl-5-nitro-2-imidazolyl)pyrazole-4-carboxamide.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.O[CH2:13][C@H:14]1[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O.CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:13][C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(I)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.1 %

Procedure:
Into a 1 L, 2-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (10 g, 38.31 mmol, 1.00 equiv), tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (15.4 g, 76.52 mmol, 2.00 equiv), PPh3 (20.1 g, 76.63 mmol, 2.00 equiv), and N,N-dimethylformamide (400 mL). DIAD (15.5 g, 76.65 mmol, 2.00 equiv) was added dropwise over 30 min. The resulting solution was stirred for 12 h at 25° C. and then diluted with 1 L of water. The resulting solution was extracted with ethyl acetate and the organic layers combined and washed with brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum and the residue was placed on a silica gel column and eluted with chloroform/methanol (100/1) to give 1.2 g (6%) of tert-butyl (2R)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate as a off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[N:38]1([C:44](=[O:46])[CH3:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CN(C=O)C>[C:44]([N:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=2[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:12]=2)=[O:9])[CH2:40][CH2:39]1)(=[O:46])[CH3:45]
Reactant: CC(=O)N1CCNCC1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(CCOc2cc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)ccc2CS(C)(=O)=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (50 mg, 0.095 mmol) was dissolved in DMF (1.0 ml) and treated with potassium carbonate (18 mg, 0.13 mmol) and 1-(piperazin-1-yl)ethanone (15 mg, 0.11 mmol) for 18 hours. The reaction was heated for 2.0 hours at 50° C., then additional potassium carbonate (18 mg, 0.13 mmol) and 1-(piperazin-1-yl)ethanone (15 mg, 0.11 mmol) was added. After 2 hours, the reaction was quenched in 5% NaOH and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and purified by reverse phase HPLC to yield 18 mg of 3-(2-(4-acetylpiperazin-1-yl)ethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 543 (M)+.